Developmental brain malformations are at the core of significant neurological diseases affecting many families in the United States and around the world. It is known that epilepsy, specific learning deficits and mental retardation, cerebral palsy, and abnormalities of brain volume can be attributed in many cases to pathological malformations of the cerebral cortex. Although these consequences, such as epilepsy and mental retardation, may appear broadly in the population as due to complex traits, our focus on those associated with cortical malformations highlights individual developmental pathways likely represented by innumerable and rare Mendelian alleles. Research of ours and others in this field have thus far uncovered dozens of genes responsible for these conditions and dissected the mechanisms underlying early cortical development in animals. However, this progress represents only the dawn of understanding the complex genetic network and neuronal architecture of the uniquely human cerebral cortex. The overall goal of our research is to continue to define the genetic bases of abnormal human cerebral cortical development. This is achieved through 1] ascertaining families with inherited brain malformations and categorizing these using neuroimaging data, 2] mapping and identifying the gene causing the characterized malformation, and 3] describing its expression and function. Ascertainment of families is focused in the Middle East and surrounding regions where the prevalence of intra-familial marriage and large family size enriches this population for rare Mendelian disorders, thereby offering significant power to distinguish gene targets through homozygosity mapping. Using the knowledge so gained, smaller families collected from Western countries are incorporated for additional weight and relevance. The causative gene is then defined with new high-throughput sequencing technologies and further characterized with animal modeling for translation to a human understanding. The discovery of new genes causing abnormal brain development impacts human health in several ways: the process provides insight into classification and diagnosis of these conditions that can be quickly translated to clinical practice; improved genetic counseling and testing can be made available to concerned families; and an enhanced understanding of the underlying molecular processes of the developing human brain can inform the conception of potential future therapies or interventions. Hence, our research works to reduce the burden of neurologic disease on our human society and does so with important short and long-term implications. PUBLIC HEALTH RELEVANCE: The formation of the human brain is a complicated and poorly understood process and problems such as seizures and learning disabilities can result when the brain does not develop properly. Our research aims to better understand how the brain develops by discovering genes that cause differences in brain formation in families around the world. Gene discovery can lead to better medical diagnosis, management and possible treatment of these often devastating conditions.